In order to elucidate neurochemical alterations associated with defective brain development, it is proposed to study the influence of experimental cretinism on the metabolism and deposition of biogenic monoamines in the rat central nervous system. The ontogenesis of dopamine, norepinephrine and serotonin in discrete regions (brain stem, basal ganglia and hypothalamus) of the normal rat brain will be compared with that in cretinous rats and in animals made hyperthyroid at birth. The ability of thyroid hormone replacement therapy to restore normal brain amine levels in cretinous rats will be studied. It is also proposed to investigate the possibility that the age of the cretinous animal influences the restorative effect of thyroid hormone on biogenic amines in the central nervous system. Attempts will be made to determine the mechanisms responsible for the alterations in these brain amines in cretinous animals. A comparison of the turnover rates of brain dopamine, norepinephrine and serotonin will be made in 30-day-old cretinous rats and in control littermates. Cretinism-induced changes in the activities of brain enzymes of monoamine synthesis (tyrosine hydroxylase) and degradation (monoamine oxidase and catechol-o-methyl transferase) will be examined. Studies on the influence of experimental cretinism on the synaptosomal uptake of dopamine, serotonin and norepinephrine will also be undertaken.